The mission of NINDS is to reduce the burden of neurological disease. Stroke is a leading cause of mortality and disability, affecting 795,000 people annually in the US at a direct and indirect cost of $38.6 billion. Stroke i a rapidly progressive disorder, with brain damage being near complete by 3 hours after stroke onset. There is a major unmet need for safe stroke treatments to reduce the burden of stroke and improve stroke victims' outcomes. We will address this need by developing an emergency stroke medication that is safe enough to be given to stroke victims in the community even before arrival to a hospital (e.g., by paramedic), or immediately on hospital arrival, thus arresting stroke progression within the first golden hour and preferaby no later than 3h after stroke onset. This will be achieved by developing a safe and effective drug that targets neuronal postsynaptic density 95 protein (PSD95), termed a PSD95 inhibitor. We have already developed a prototype (termed NA-1) that reduces stroke damage in animals and humans, but that has the side effect of producing hypotension. This makes NA-1 unsuitable for use in emergency situations. To improve on NA-1 we identified 7 potential related candidates. Our objective is to evaluate each in order to select the optimal Lead Candidate for further development in future clinical trials. This will be done through the followin steps: In vitro lead selection: The 7 candidates will be evaluated in vitro for optimal properties that are predictive of efficacy in animal stroke models and for clinical utility; Lad selection in animals: The same candidates will be evaluated in rats for lack of hypotension and then advanced to more detailed animal studies that include evaluations of the drugs' efficacy in experimental strokes. The most effective and safe single candidate will be advanced to the next steps; Manufacturing and formulation studies: The lead PSD95 inhibitor will be manufactured to regulatory (FDA/ICH) standards and used to create a formulation in a drug vial that protects the drug from degrading and that can be used in an ambulance or a hospital; Safety Pharmacology and Toxicity testing. This lead candidate will then be tested in the necessary studies to demonstrate safety in animals, and to confirm that it is appropriate for advancement to a filing of an IND for a Phase 1 human trial. Filing of an IND: The project will culminate with a filing of an IND with the FDA for a Phase 1 human trial. We have already successfully translated NA-1 all the way from its discovery to a successfl phase 2 human clinical trial and are experienced in the process of developing a PSD95 inhibitor and the filing of IND submissions. We are thus confident that this project will provide a safe emergency neuroprotectant for further development in order to reduce the extraordinary burden of stroke on our society.